Reg3β deficiency impairs pancreatic tumor growth by skewing macrophage polarization

The lectin Reg3β provides crucial protection to various tissues against inflammation, a potential risk factor for pancreatic ductal adenocarcinoma. Reg3β is also overexpressed in serum and pancreatic juice from patients with this cancer, but its function in this context remains to be elucidated. In this study, we investigated the role of Reg3β in tumor development in an orthotopic mouse model of pancreatic cancer. Reg3β deletion in mice drastically impaired pancreatic tumor growth, correlating with decreased angiogenesis and increased apoptosis of tumor cells. Moreover, Reg3β deficiency resulted in an alteration of the tumoral immune microenvironment, reflected by a decrease in the M2/M1 ratio of tumor-associated macrophages and an upregulation of CD3(+) cell infiltration. Addition of Reg3β to prestimulated RAW 264.7 or primary macrophages enhanced M2 polarization through the activation of STAT3 signaling pathway. Conditioned media from Reg3β-M2-polarized primary macrophages inhibited apoptosis and prolonged the viability of Panc02 tumor cells. Our studies reveal a novel role for Reg3β as a tumor promoter in pancreatic adenocarcinoma through the regulation of tumor stroma. Thus, inhibition of this protein may be a useful strategy in treatment of pancreatic cancer.